A Novel Role for IGF-1 Receptor in Growth Hormone Action

IGF-1 受体在生长激素作用中的新作用

• 批准号: 9178068
• 负责人: Stuart J Frank
• 金额: $ 33.08万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9178068
• 关键词: Acute; Address; Alpha Cell; Area; Binding; Biological Assay; Bioluminescence; Cancer Biology; Cells; Chimera organism; Collaborations; Complement; Coupled; Coupling; Cytokine Receptors; Data; Dominant-Negative Mutation; Down-Regulation; Elements; Endocrine; Extracellular Domain; Extrahepatic; Functional disorder; Gene Expression; Genes; Growth; Growth Disorders; Growth Hormone Receptor; Hepatic; Hormone Responsive; In Vitro; Insulin Receptor; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Islet Cell; JAK2 gene; Knock-out; Knowledge; Liver; Luciferases; Mediating; Medicine; Metabolic; Metabolic Diseases; Metabolism; Methods; Modeling; Mus; Mutagenesis; Osteoblasts; Outcome; Pancreas; Pathway interactions; Phosphotransferases; Physiological; Physiology; Production; Protein Tyrosine Kinase; Proteins; Proteomics; Recombinants; Regulation; Reporting; Role; Signal Transduction; Somatomedins; Somatotropin; Stat5 protein; System; Testing; Therapeutic; Tissues; Work; base; cell type; glucose metabolism; hormone sensitivity; in vivo; member; metabolic phenotype; mutant; novel; novel strategies; novel therapeutics; prostate cancer cell; public health relevance; receptor; receptor binding; reconstitution; response

 DESCRIPTION (provided by applicant): Growth hormone (GH) regulates growth and metabolism by binding GH receptor (GHR), a cytokine receptor superfamily member, in target tissues. This activates the GHR-associated cytoplasmic tyrosine kinase, JAK2, and several signaling systems including STAT5. An important GH-induced outcome in some cell types is STAT5-mediated expression of the insulin-like growth factor (IGF)-1 gene and IGF-1 secretion. For six decades, our appreciation of GH physiology has been influenced by the somatomedin hypothesis, which held that GH-induced hepatically-derived circulating endocrine IGF-1 (aka somatomedin-C) mediates GH's somatogenic actions. Indeed, IGF-1 acts via the type 1 IGF-1 receptor (IGF-1R) to transmit tyrosine-kinase-mediated anabolic signals. However, our novel findings suggest IGF-1R also functions in relevant cell types (preadipocytes, islet -cells, osteoblasts, prostate cancer cells) as a proximal GHR-interacting element to augment GH sensitivity, even absent IGF-1 binding. Specifically, we find GH acutely promotes IGF-1R association with GHR and that IGF-1R deletion reduces acute GH signaling and consequent IGF-1 gene expression. IGF-1R reconstitution in IGF-1R-deleted cells rescues GH responsiveness in a fashion that depends on IGF-1R extracellular domain (ECD) elements. Further, a recombinantly-produced soluble IGF-1R ECD fragment containing these elements binds GHR in response to GH and blunts GH-induced signaling and gene expression in a dominant-negative fashion. Supporting our findings, recent reports indicate overlap in the metabolic phenotypes of mice with islet -cell-specific deletion of either GHR or IGF-1R, suggesting GHR-IGF-1R interaction is physiologically relevant in cell types that coexpress the receptors, unlike liver that is heavily endowed with GHR, but nearly devoid of IGF-1R. We hypothesize: 1) IGF-1R, by virtue of specific interaction with GHR, augments GH-induced somatogenic and metabolic signaling in a physiologically-relevant fashion. 2) Modulation of GHR-IGF-1R interaction could be a therapeutically-relevant target to promote or inhibit GH actions, particularly in non-hepatic tissues that express IGF-1R and when IGF-1R is aberrantly expressed in liver. Specific aims: 1) Define elements in IGF-1R that allow transmembrane-anchored IGF-1R to augment GH signaling; 2) Uncover specific modulators of GH action based on dominant-negative effects of soluble IGF-1R on GH signaling; 3) Examine functional effects of IGF-1R on GHR action in liver and pancreatic -cells in in vivo systems. Proposed studies address a fundamentally novel hypothesis about how GH-induced GHR action is influenced by physical and functional coupling of GHR with IGF-1R and IGF-1R-associated molecules. Our discoveries will enrich the "linear" GHGHRIGF-1IGF-1R pathway (somatomedin hypothesis), suggesting "parallel" GHR/IGF-1R-mediated effects, especially in extrahepatic GH action. Relationships of this work with aspects of metabolic regulation and other areas, including growth disorders and cancer biology, could be many and our results may suggest novel strategies to modulate GH action.